Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation

N. Henriette Uhlenhaut; Susanne Jakob; Katrin Anlag; Tobias Eisenberger; Ryohei Sekido; Jana Kress; Anna-Corina Treier; Claudia Klugmann; Christian Klasen; Nadine I. Holter; Dieter Riethmacher; Guenther Schutz; Austin J. Cooney; Robin Lovell-Badge; Mathias Treier

doi:10.1016/j.cell.2009.11.021

Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation

N. Henriette Uhlenhaut, Susanne Jakob, Katrin Anlag, Tobias Eisenberger, Ryohei Sekido, Jana Kress, Anna-Corina Treier, Claudia Klugmann, Christian Klasen, Nadine I. Holter, Dieter Riethmacher, Guenther Schutz, Austin J. Cooney, Robin Lovell-Badge, Mathias Treier^*

^*Corresponding author for this work

Medical Sciences

Research output: Contribution to journal › Article › peer-review

797 Citations (Scopus)

Abstract

In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.

For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Original language	English
Pages (from-to)	1130-1142
Number of pages	13
Journal	Cell
Volume	139
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2009.11.021
Publication status	Published - 11 Dec 2009

Funding

We thank the staff of the EMBL Laboratory Animal Resources for expert animal husbandry, and S. Fehsenfeld and T. Ivacevic for technical assistance. We thank A. F. Parlow at the National Hormone and Peptide Program; HUMC for help with serum testosterone measurements; and M. Wegner and D. Zarkower for SOX9 and DMRT1 antibodies. This work was supported in part by the Deutsche Forschungsgemeinschaft (DFG-TR341, M. T.) and by the MRC (U117512772) and Louis Jeantet Foundation (S.J., R. S., and R. L. B.).

Keywords

beta-catenin
transcription factor FOXL2
germ-cells
reversal
mammalian gonad
sry action
pre-sertoli cells
SOX9
differentiation
gene-transcription

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title = "Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation",

abstract = "In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.",

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AU - Uhlenhaut, N. Henriette

AU - Jakob, Susanne

AU - Anlag, Katrin

AU - Eisenberger, Tobias

AU - Sekido, Ryohei

AU - Kress, Jana

AU - Treier, Anna-Corina

AU - Klugmann, Claudia

AU - Klasen, Christian

AU - Holter, Nadine I.

AU - Riethmacher, Dieter

AU - Schutz, Guenther

AU - Cooney, Austin J.

AU - Lovell-Badge, Robin

AU - Treier, Mathias

PY - 2009/12/11

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N2 - In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

AB - In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

KW - beta-catenin

KW - transcription factor FOXL2

KW - germ-cells

KW - reversal

KW - mammalian gonad

KW - sry action

KW - pre-sertoli cells

KW - SOX9

KW - differentiation

KW - gene-transcription

U2 - 10.1016/j.cell.2009.11.021

DO - 10.1016/j.cell.2009.11.021

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SP - 1130

EP - 1142

JO - Cell

JF - Cell

IS - 6

ER -

Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation

Abstract

Funding

Keywords

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